Chemical research today is the foundation of many industries, not the least of which are those that develop and market pharmaceuticals. The pharmaceutical marketplace is not only very competitive and profitable for those who are successful, but success in discovering and synthesizing new medicines also enhances the safety, health, and well being of people everywhere.
In the processes of chemical investigation, as in most other technical areas, the rapid growth of computer arts and science has brought new tools and techniques, and advanced the ability of researchers to accomplish their goals. In particular, in chemistry, computer graphics technologies have provided new ability to display and manipulate models of newly proposed chemical structures, and to study the projected physical behavior and interactions of such structures.
Even though computer techniques are being applied diligently to the needs of developmental chemists, or what have been called "bench" chemists in the art, the integration of computer techniques and traditional chemical procedures has not been without difficulty. One problem, as is true in many other fields, is that traditional chemists are not computer scientists, and have not been trained to be such. Traditional training for chemists still emphasizes, as it must, concepts of chemical bonding of atoms and molecules, the dynamics of the resulting structures, and interaction with other compounds. The computer tools that are currently available have many shortcomings, including that they are not very intuitive for persons trained in chemistry.
Although there have been advances in three-dimensional computer modeling techniques, and many have been applied to modeling the structure of chemical compounds, traditional chemistry still relies on two-dimensional representation of chemical connectivity and topology, even though the representations can only be approximate and stylized. One good reason is that textbooks are not capable of economic three-dimensional representations, particularly not dynamic representations, and the chemical literature (recorded knowledge) of the past, on which new developments of necessity must rest, is in two-dimensional representation. Moreover, over the many years of development in the chemical arts, standardized ways of representing chemical structures, bonds, and the like have been widely accepted and provide the foundation of cognition of structural similarity in the chemical sciences.
A chemist involved in a search for new compounds, for instance, gravitates to techniques that utilize two-dimensional material. Such material and technique, however, leave out a multitude of important information about a chemical structure, and some of that information can be absolutely critical to decisions shaping an investigation. For example, many chemical reactions rely on molecular shape (spatial or volumetric properties), rather than two-dimensional topology, valency, or other conventional properties. Enzyme-catalyzed reactions in biochemistry are an example. Enzymes interact with substrates as a result of complicated "lock and key" shapes that fit together--that are a partly a function of three-dimensional molecular shape.
A related difficulty stems from the fact that chemical compounds do not exist in just a single geometric conformation. Many molecular bonds are not static and immovable, but rather are rotatable and stretchable, giving rise to many different geometric arrangements (conformers) for a compound, some more stable than others. Where there are rotatable bonds, the number of conformers is infinite.
The very large number of different geometric conformations that molecules may assume cannot be safely ignored in any chemical investigation, because of the complex relationship between the different conformers and the observed reactivity, efficacy, etc. of a compound. Moreover, the conformational changes are extremely rapid, and a molecule typically assumes many different conformations over periods of time measured in pico-seconds. The study and investigation of such perturbations is called molecular dynamics, and lends itself handily to statistical analysis and computer techniques. A typical procedure in molecular dynamics involves many hours of supercomputer time to simulate and analyze changes that occur in a molecule in a pico-second.
One way that computers have been incorporated into chemical investigation has been by interaction between bench chemists and specialists trained and experienced in computer graphics and molecular dynamics. A single research organization, for example, might have traditional synthetic/medicinal chemists engaged in studying problems and proposing chemical solutions, such as new compounds to be synthesized. In another department, trained computer molecular modelers accept information from the traditional chemists and perform molecular modeling and dynamics studies.
Such cooperative approaches have had some success, but generally suffer from communications difficulties. Perhaps more importantly the research chemist is distanced from tools that could provide valuable insight on a moment-to-moment basis and which could more positively influence the direction and impact of a study.
Another approach used by the bench chemist to query three-dimensional chemical structures has been the use of metal and plastic physical models of molecules and compounds, connected by mechanisms that represent to some degree the natural connections. Springs can be used, for example, to preload structures and represent the forces inherent in a molecular system. Flexible materials are also useful. Such physical models have an advantage of hands-on feel, and are easily rotated, translated, and manipulated. As the size of a structure under scrutiny increases, however, such physical models become unwieldy and cumbersome, and the forces acting on various parts of a molecule are increasingly difficult to perceive, even approximately. Moreover, such models have no mechanism for representing the energy of various geometries of a molecular structure, and hence no way to incorporate molecular dynamics in a really useful way. The plastic and metal models also have no convenient mechanism for representing Van der Waals or electrostatic forces.
Yet another difficulty with techniques of the prior art is that where attempts have been made to computerize modeling and dynamics, the complexity of molecular structures and the forces between atoms in the molecules has required computers of considerable power and sophistication to provide modeling. There has been but little progress in reducing the magnitude of computer power needed to accomplish useful modeling techniques.
What is clearly needed to overcome these many difficulties is a comprehensive computerized system that allows a bench chemist to use both two-dimensional and three-dimensional representations, allowing input in either format, storing data for both formats, and updating displays in both formats as data changes. Ideally, such a system needs to come as close to "hands-on" manipulation as possible. The user, who will frequently be called the investigator in this specification, must be able to work in either the two-dimensional or the three-dimensional format as the need arises for a single situation, choosing that format that has the best advantage for the moment, and best matches the mental process of the investigator at that point in time. For example, setting up a structure from more elemental forms, such as assembling a compound from traditional ring structures, common substituent groups, and atoms, is best done in a two-dimensional format, following the traditional connectivity standards known in the art. Examining the volumetric shapes of a resulting structure is best done in a three-dimensional format with an ability to rotate, translate, and otherwise manipulate the model.
A system to be very useful directly by a bench chemist should comprise a facility for allowing the chemist to manipulate portions of a connected structure, such as rotating and bending bonds, within the constraints imposed by the known connective chemistry and the forces attendant according to the laws of physics relative to the structure. Moreover, as such manipulation is accomplished, the system should readily determine relative energies and related stability of the new physical configurations resulting from the manipulation. This facility would allow a chemist a truly interactive method for investigating alternative conformers of a compound without the time-consuming and very expensive application of supercomputer hardware, massive computational techniques, and employment of computer applications experts common to the current art of molecular modeling.
Another desirable feature of such a system would be an ability to display more than one molecule simultaneously and to allow a user to study docking characteristics relative to the displayed molecules, such as "lock and key" complementarity.